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CLINICAL OVERVIEW

Influenza
Elsevier Point of Care (see details)
Updated April 26, 2019. Copyright Elsevier BV. All rights reserved.

Synopsis Urgent Action

Key Points Identify patients at higher risk of
Influenza causes seasonal epidemics of an acutely debilitating febrile complications and start
respiratory illness of up to 2 weeks in duration neuraminidase treatment as
soon as possible
During epidemics, recognition of the classic symptoms of abrupt onset of
high fever, myalgia, headache, and cough is diagnostic for most patients. Hospitalize very young children,
Confirm with rapid diagnostic tests in patients with high medical risk. elderly people, and pregnant
Laboratory testing (viral culture) is most useful in nonepidemic settings or women if illness is severe or is
for epidemiologic uses rapidly worsening

Yearly influenza vaccine is recommended for all persons older than 6

months 1

Special caution is needed in those with severe egg allergy; the vaccine is contraindicated in persons who have
previously experienced an allergic reaction to influenza vaccine

Prophylactic use of neuraminidase inhibitors is indicated in some situations (eg, high medical risk)

Persons at higher risk for severe illness and complications (eg, viral or bacterial pneumonia) include children
younger than 5 years, adults older than 65 years, pregnant women, and those with many chronic medical
conditions 2

Treatment of influenza with neuraminidase inhibitors is recommended for these patients and for all patients
who have severe or progressive illness or are hospitalized with influenza

Neuraminidase treatment is best begun within 48 hours of illness but may be beneficial up to day 5 3

Treatment is primarily supportive for persons without severe disease and without elevated risk of complications

Pitfalls
Not all vaccine formulations are approved for all age groups; be sure to select an age-appropriate product

Egg allergy is not a contraindication for seasonal influenza vaccine 1

Recombinant hemagglutinin influenza vaccines, available in trivalent and quadrivalent formulations, are
considered egg free

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Persons whose allergic reaction to eggs is limited to hives may receive any age-appropriate, inactivated-virus
vaccine

Persons who have experienced more severe reactions to eggs (eg, angioedema, respiratory distress) may receive
any age-appropriate inactivated vaccine in a health care setting under supervision of a provider experienced in
managing severe allergic reactions

A previous severe allergic reaction to influenza vaccine, regardless of the component suspected of being
responsible for the reaction, is a contraindication to future receipt of the vaccine

Terminology
Clinical Clarification
Influenza is an acute, seasonally epidemic, highly contagious, febrile respiratory illness caused by infection with
influenza virus

Classification
By type: 4

Influenza A and B cause most clinical disease in humans; type C rarely causes significant illness

Influenza A viruses are named according to viral surface hemagglutinin (H or HA) and neuraminidase (N or
NA) antigens, geographic area of origin, isolate number, and year of isolation (eg, A/Texas/50/2012 for a
variant of H3N2)

Influenza B viruses are named by lineage (eg, B/Victoria)

Diagnosis
Clinical Presentation
History
Presentation varies from mild to profound and life-threatening illness

Abrupt onset of symptoms is a hallmark of influenza, beginning 1 to 4 days after exposure and lasting up to 14
days

First symptoms typically include:

Fever, chills, and diaphoresis (common)

Myalgia (may be intense)

Headache (often prominent)

Malaise and fatigue (may be profound)

Anorexia (common)

Subsequent symptoms may include the following respiratory tract complaints:

Rhinorrhea and nasal congestion, with or without sneezing (prominent)

Sore throat (common)

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Deep, hacking, nonproductive cough resulting in progressive chest discomfort

Dyspnea may be present with influenzal pneumonia

Gastrointestinal symptoms (eg, nausea, vomiting, diarrhea) occur sometimes in children but rarely in adults

Physical examination
Fever is usual but is less common in children and elderly people

Tachycardia may be present if fever is high or patient is dehydrated

Tachypnea may indicate pneumonia or more severe disease

Erythema of nasal and oropharyngeal mucous membranes

Thin nasal discharge

Cervical adenopathy (usually posterior)

Lung examination may find clear lungs; rales or rhonchi suggest viral or secondary bacterial pneumonia

Causes and Risk Factors

Causes
1 or 2 strains of influenza A and B cause seasonal epidemics each year; type C strains cause only sporadic illness

Risk factors and/or associations

Age
Rates are higher in children than in adults, but all ages are affected 4

Elderly people are also at higher risk 4

Other risk factors/associations

Seasonal pattern

Occurs from mid-fall to early spring in temperate climates

Seen sporadically throughout the year in tropical climates

Risk factors for severe manifestations:

Immunocompromised status

Comorbid chronic illness (eg, diabetes; heart failure; chronic pulmonary, renal, hepatic, hematologic, or
neurologic disease)

Morbid obesity

Pregnancy

Diagnostic Procedures
Primary diagnostic tools

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History and physical examination are usually sufficient to make the diagnosis in the setting of seasonal
epidemics 5 6

Use rapid molecular assays (ie, nucleic acid amplification tests) over rapid influenza diagnostic tests in
outpatients to improve detection of influenza virus infection 2

Use reverse-transcription polymerase chain reaction (or other molecular assays) over other influenza tests in
hospitalized patients to improve detection of influenza virus infection 2

Use multiplex reverse-transcription polymerase chain reaction assays targeting a panel of respiratory
pathogens, including influenza viruses, in hospitalized immunocompromised patients 2

Consider using multiplex reverse-transcription polymerase chain reaction assays targeting a panel of
respiratory pathogens, including influenza viruses, in hospitalized patients who are not
immunocompromised if results might influence care

Do not use immunofluorescence assays for influenza virus antigen detection in hospitalized patients except
when more sensitive molecular assays are not available; follow-up testing with reverse-transcription
polymerase chain reaction or other molecular assays should be performed to confirm negative
immunofluorescence test results 2

Do not use rapid influenza diagnostic tests in hospitalized patients except when more sensitive molecular
assays are not available; follow-up testing with reverse-transcription polymerase chain reaction or other
molecular assays should be performed to confirm negative rapid influenza diagnostic test results 2

Laboratory

Imaging

Differential Diagnosis
Most common

Common cold
Prevalent during winter months, overlapping with influenza epidemics

Clinically, onset is more gradual, and patient appears only mildly ill

Fever is absent or lower than with influenza; patients are less likely to
have severe myalgia and fatigue

Predominant symptoms are in upper respiratory tract in common cold, as

opposed to lower respiratory tract (eg, cough) in influenza

Diagnostic groups

Other respiratory tract viral infections

Respiratory syncytial virus infection

Seasonality overlaps that of influenza; infection mostly affects infants and small children

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Often nosocomial (patients develop symptoms after being in a health care environment)

Lower respiratory tract symptoms predominate, with prolonged expiratory phase, rales, and wheezes

Diagnosis is confirmed by polymerase chain reaction assay

Parainfluenza virus infection

Seasonality overlaps that of influenza; infection causes both upper and lower respiratory tract disease in
infants and small children and mostly upper respiratory tract disease in adults

Croup and hoarseness are predominant symptoms

Diagnosis is confirmed by polymerase chain reaction assay or antigen detection test

Adenovirus infection

Usually not seasonal; more common in children

Most prominent symptoms are sore throat, hoarseness, and conjunctivitis

Diagnosis is confirmed by polymerase chain reaction assay or antigen detection test

Epstein-Barr virus infection

Occurs sporadically (not seasonally); most common in adolescents and young adults

Most prominent symptoms are sore throat and fatigue; physical findings include pharyngeal exudates and
prominent posterior cervical adenopathy; cough is not predominant symptom

Diagnosed by laboratory testing (monospot rapid test or Epstein-Barr virus antibody testing)

Bacterial infections

Pneumonia (Related: Community-acquired pneumonia in adults)

May occur sporadically or may be a complication of influenza

Symptoms are similar, but cough is productive and there is more likelihood of pleuritic chest pain and
dyspnea

Rales and rhonchi, egophony, and/or dullness to percussion suggest a pneumonic infiltrate

Diagnosed by chest radiograph and microscopy and culture of sputum

Meningococcal meningitis (Related: Bacterial meningitis in adults)

Tends to occur in epidemics; occurs most commonly in children and young adults living in close quarters (eg,
dormitories, barracks) (Related: Bacterial meningitis in children)

Begins abruptly, as influenza does, and with high fever

Predominant symptoms initially are severe headache, neck stiffness, photophobia, and vomiting

Rash may be present; cough is unusual

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Diagnosis is confirmed by cerebrospinal fluid analysis and culture

Treatment
Goals
Relieve symptoms

Prevent complications (eg, viral pneumonia) in patients at higher risk

Disposition
Admission criteria
Admit pregnant women, children younger than 5 years, and adults older than 65 years with severe illness or with
moderate illness that appears to be rapidly worsening

Criteria for ICU admission

Patients likely to need ventilator support

Severe or rapidly progressive illness with dyspnea and/or hypoxia

Bilateral diffuse pneumonia

Patients with hemodynamic instability

Recommendations for specialist referral

Refer to an infectious disease specialist, pulmonologist, or critical care specialist for severe illness requiring
hospitalization

Consider consultation with an allergist for high-risk patients who would benefit from immunization but are
allergic to the vaccine

Treatment Options
Supportive care with rest and maintenance of adequate hydration

Common symptomatic treatments involve relief of fever, pain, and nasal congestion (eg, OTC forms of NSAIDs
are often used; avoid aspirin in children owing to risk of Reye syndrome)

Neuraminidase inhibitors are recommended as soon as possible with confirmed or suspected influenza for the
following 3 groups of patients: 7 9

Patients with severe or progressive illness 2

Hospitalized patients 2

Patients at high risk of complications 2

Children younger than 5 years (especially those younger than 2 years 2 )

Adults aged 65 years and older 2

Residents of nursing homes and other long-term care facilities

Persons with certain medical conditions or demographic characteristics, as follows:

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Asthma and other chronic pulmonary diseases

Cardiovascular disease (except hypertension alone)

Renal disease

Hepatic disease

Hematologic conditions (including sickle cell disease)

Immunosuppression due to medication, HIV infection, or other causes

Long-term aspirin therapy if younger than 19 years

Metabolic disorders (including diabetes mellitus)

Neurologic and neurodevelopmental conditions

Morbid obesity (BMI of 40 kg/m² or more)

Pregnant or recent (within 2 weeks) postpartum status 2

American Indian or Alaska Native ethnicity

Decision to administer therapy need not depend on test results 3

In particular, in very ill patients or those at high risk, do not delay treatment while awaiting test results

Drug therapy
Neuraminidase inhibitors

May be prescribed electively for healthy adults and children not at high risk of complications; associated with
small decrease in length of illness in adults; results in children are inconsistent 10

Observational studies of hospitalized children and adults suggest that significant decrease in mortality is most
pronounced when an inhibitor is started within 48 hours 11 12 13

If treatment is elected, start antiviral treatment as soon as possible after illness onset, 2 ideally within 48 hours
of symptom onset, and continue for 5 days 2 3 14

In hospitalized or otherwise severely ill patients, institute treatment regardless of duration of symptoms

Oseltamivir is favored over zanamivir in this population

For patients unable to absorb oseltamivir because of gastrointestinal malfunction, IV peramivir may be
administered

If oseltamivir resistance is suspected, IV zanamivir (an investigational formulation) is an option

Extended courses may be considered for patients who remain severely ill

Oseltamivir 15

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Oseltamivir Phosphate Oral suspension; Premature Neonates younger than 38 weeks postmenstrual age†: 1
mg/kg/dose PO twice daily for 5 days; consider extended course for severely ill patients.

Oseltamivir Phosphate Oral suspension; Premature Neonates 38 to 40 weeks postmenstrual age†: 1.5
mg/kg/dose PO twice daily for 5 days; consider extended course for severely ill patients.

Oseltamivir Phosphate Oral suspension; Premature Neonates older than 40 weeks postmenstrual age† and
Term Neonates 0 to 13 days†: 3 mg/kg/dose PO twice daily for 5 days; consider extended course for severely
ill patients.

Oseltamivir Phosphate Oral suspension; Term Neonates 14 to 29 days: 3 mg/kg/dose PO twice daily for 5
days; consider extended course for severely ill patients.

Oseltamivir Phosphate Oral suspension; Children weighing 15 kg or less: 30 mg PO twice daily for 5 days;
consider extended course for severely ill patients.

Oseltamivir Phosphate Oral suspension; Children weighing 16 to 23 kg: 45 mg PO twice daily for 5 days;
consider extended course for severely ill patients.

Oseltamivir Phosphate Oral suspension; Children weighing 24 to 40 kg: 60 mg PO twice daily for 5 days;
consider extended course for severely ill patients.

Oseltamivir Phosphate Oral capsule; Children weighing more than 40 kg and Adolescents: 75 mg PO twice
daily for 5 days; consider extended course for severely ill patients.

Zanamivir

Inhaled

Infants and children younger than 7 years: Safety and efficacy have not been established. Clinical studies
have indicated that young children do not produce the peak inspiratory flow rates needed for the proper
use of dry powder inhalers such as the Diskhaler device, which limits the systemic absorption and clinical
efficacy of zanamivir.

Zanamivir Inhalation powder; Children and Adolescents 7 to 17 years: 2 inhalations (one 5-mg blister per
inhalation for total dose of 10 mg) PO 2 times daily (roughly every 12 hours) for 5 days. Take 2 doses on
first day provided there are at least 2 hours between doses. CDC suggests potential longer treatment course
in severely ill.

IV

Available only through enrollment in an ongoing clinical trial or through a compassionate use program;
follow dosage recommendations from the clinical trial or provided by the manufacturer

Peramivir

Peramivir Solution for injection; Adults: 600 mg IV as a single dose. Administer within 48 hours of influenza
symptom onset.

Nondrug and supportive care

Rest and adequate fluid intake to offset insensible losses during fever are recommended

Special populations

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Pregnant women

Increased risk for hospitalization but not mortality 16

Increased risk of preterm birth and small-for-gestational-age infants

All women who are or will be pregnant during influenza season should receive an inactivated influenza vaccine
as soon as it is available 17

Any of the recommended, age-appropriate, inactivated influenza vaccines can be given in any trimester

Live attenuated influenza vaccine is not recommended for use during pregnancy

All pregnant women with clinically suspected or confirmed influenza should be treated with antiviral
medication, regardless of vaccination status or laboratory test results 18

Use oseltamivir or zanamivir based on current local resistance patterns

Start treatment within 48 hours of symptom onset if possible

However, it is recommended that these drugs be started even if the 48-hour mark has passed

Hospitalize pregnant women if illness appears to be severe or is worsening, with a low threshold for admitting
to ICU with signs of respiratory distress

Consider postexposure chemoprophylaxis in pregnant women and those up to 2 weeks postpartum (including
after pregnancy loss) who have had close contact with influenza patients 18

Administer within 48 hours of exposure 19

Complications and Prognosis

Complications
Direct influenza virus complications

Influenzal pneumonia is the most common viral complication

Rarely, the following may occur:

Aseptic meningitis and/or encephalitis

Myositis and/or rhabdomyolysis

Transverse myelitis

Suppurative complications

Bacterial pneumonia

Otitis media

Sinusitis

Worsening of comorbid conditions

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Asthma

Chronic obstructive pulmonary disease

Congestive heart failure

Prognosis
For patients in low-risk groups who do not develop complications, prognosis is good and a full recovery is
expected

Patients in high-risk groups have an increased incidence of severe illness, hospitalization, and death

Overall mortality is 1.4 deaths per 100,000 population in the United States 20

Screening and Prevention

Prevention
Vaccination

Seasonal influenza vaccine is recommended yearly, in autumn, for all persons aged 6 months and older
(including pregnant women) for whom there is no contraindication 1 21

Children aged 6 months through 8 years require 2 doses of influenza vaccine (administered 4 or more weeks
apart) during their first season of vaccination to optimize immune response 1

Children aged 6 months through 8 years who have received 2 or more doses of trivalent or quadrivalent
influenza vaccine previously (regardless of whether they were given during the same season or consecutive
seasons) do not require 2 doses of vaccine

Children who have received only 1 vaccine dose in a previous season should receive the 2-dose initial
regimen; the interval between the 2 doses should be at least 4 weeks

3 types of vaccines are produced in the United States 1

Inactivated influenza virus vaccine, available in trivalent and quadrivalent forms: for patients aged 6 months
and older

Not all commercially available vaccines are approved for all age groups

High-dose trivalent and adjuvanted trivalent forms are available for adults older than 65 years

There is some evidence that these may be more effective than standard-dose inactivated vaccine;
however, based on existing data, the Advisory Committee on Immunization Practices of the CDC does
not favor any particular available age-appropriate preparation

Recombinant hemagglutinin influenza vaccine, available in trivalent and quadrivalent formulations for
patients aged 18 years and older

Live attenuated influenza vaccine, quadrivalent (administered intranasally)

After several seasons during which this formulation was not recommended in the United States, the
vaccine has been modified and is a recommended option for healthy nonpregnant persons aged 2 through

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49 years during the 2018-2019 season 1

Egg allergy is not a contraindication to influenza vaccine 1

Persons with a history of egg allergy, regardless of severity, may receive any of the recommended age-
appropriate influenza vaccines 1

In persons who have experienced reactions more severe than urticaria (eg, angioedema, respiratory distress,
lightheadedness, recurrent emesis) or who required epinephrine or similar intervention, the vaccine should
be administered in a medical setting and supervised by a clinician able to manage severe allergic reactions

Influenza vaccine is contraindicated in persons who have experienced a severe allergic reaction to it in the past
22

Persons with a history of Guillain-Barré syndrome occurring within 6 weeks of influenza vaccine should not
receive influenza vaccine unless they are at high risk for complications from influenza, in which case benefit
may outweigh risk; antiviral prophylaxis is an alternative 1

Antiviral prophylaxis

Pre- or postexposure chemoprophylaxis with the neuraminidase inhibitors oseltamivir and zanamivir may be
given to adults and children aged 3 months or older for the following reasons: 2

In conjunction with prompt administration of inactivated influenza vaccine, protect patients who are at high
risk of developing complications from influenza in whom influenza vaccination is expected to be effective
(but not yet administered) when influenza activity has been detected in the community 2

Protect unvaccinated high-risk patients and their household contacts with recent exposure to influenza 2

Protect immunocompromised patients who cannot develop an antibody response to vaccine 2

Prevent or control large outbreaks in closed settings 2

Begin postexposure prophylaxis within 48 hours of exposure 9

Antiviral drugs may be given concurrently with inactivated influenza virus vaccine 23

Live attenuated influenza vaccine should not be administered concurrently with antiviral medication or
within 48 hours after last dose of antiviral medication

Zanamivir dosage for prophylaxis is the same as for treatment; oseltamivir prophylaxis is given once daily at
half the total daily treatment dosage 9

Duration of chemoprophylaxis varies with the circumstances, as follows: 9

Postexposure prophylaxis is usually maintained for 10 days after most recent exposure

In persons at high risk who cannot be immunized, continue preexposure prophylaxis for duration of
influenza season

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For management of institutional outbreaks, continue prophylaxis for a minimum of 2 weeks and for at least
10 days after onset of illness in the last patient

Other preventative actions 24

Hand washing with soap and water

Avoiding contact with infected persons and limiting contact with others while sick (by staying home for at least
24 hours after flulike symptoms appear)

Covering one's nose and mouth with a tissue while coughing or sneezing and throwing the tissue in the trash
after use

Avoiding touching mouth, nose, and eyes

Cleaning and disinfecting surfaces

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Copyright © 2019 Elsevier, Inc. All rights reserved.

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